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Category: genetics

Overlooked non-coding genes cause diabetes in babies, study reveals

Scientists have found new genetic causes for diabetes in babies—in a part of the genome that has historically been overlooked in genetic studies. Until recently, most research has investigated causes of disease in “coding” genes—those that produce proteins. Now, academics at the University of Exeter and their international collaborators have found that DNA changes in two genes that instead make functional RNA molecules are a cause of diabetes. RNA plays various roles in the body, including regulating genes and influencing how genetic information is “read” and interpreted.

The study is titled “Bi-allelic variants in the non-protein-coding minor spliceosome components RNU6ATAC and RNU4ATAC cause syndromic monogenic autoimmune diabetes,” and was published in the American Journal of Human Genetics.

The team used genome sequencing, a method that reads all the letters in a person’s DNA. They found that changes in two genes called RNU4ATAC and RNU6ATAC were the cause of autoimmune neonatal diabetes in 19 children.

Long non-coding RNA may be a promising therapeutic target for cancer

Northwestern Medicine scientists have discovered that a specific long non-coding RNA activates oncogenic signaling pathways in prostate cancer cells and drives tumor progression, underscoring its potential as a therapeutic target, according to a recent study published in Nature Communications. Rendong Yang, Ph.D., associate professor of Urology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, was co-corresponding author of the study.

Long non-coding RNAs (lncRNAs) are a type of RNA with transcripts that contain more than 200 nucleotides and play a central role in regulating gene expression, most notably in cancer progression. While previous work has identified many cancer-associated lncRNAs, the mechanisms by which lncRNAs influence cancer progression have remained unknown due to lncRNAs’ cell type-specific and tissue-specific gene expression patterns.

In the current study, the scientists aimed to uncover cellular interactions between super-enhancers—clusters of regulatory DNA elements that drive high levels of transcription—and lncRNAs by studying RNA sequencing data from patients with metastatic castration-resistant prostate cancer.

Tau mutation drives autophagy-lysosome dysfunction

The researchers studied a specific mutation in a brain protein called tau that causes the protein to become misfolded and alter its normal function. In general, when tau proteins become misfolded, they build up inside neurons and contribute to various forms of dementia, including Alzheimer’s dementia and frontotemporal dementia, a neurodegenerative disease similar to Alzheimer’s that often strikes earlier — in middle age — and typically involves significant changes in personality and behavior that precede cognitive decline.

In this new study, the researchers studied neurons that had been reprogrammed from skin cells sampled from patients with frontotemporal dementia who carried the tau mutation. In the neurons, the mutated tau proteins caused waste-recycling centers called lysosomes, which are involved in autophagy, to become dysfunctional, allowing cellular waste to accumulate in the lysosomes, which may contribute to neuronal death. The researchers found that enhancing autophagy with an analog of the chemical compound G2 improved clearance of the garbage, reduced tau levels in the lysosomes and prevented cellular toxicity and death.

G2 was discovered in 2019 via screening experiments seeking drugs that could reduce the accumulation of an aggregation-prone protein in a C. elegans model of alpha-1-antitrypsin deficiency, which can cause severe liver disease. The compound was later shown to boost autophagy function in mammalian cell model systems.

The researchers also have shown that G2 can protect brain cells from death in cells modeling Huntington’s disease, a fatal inherited neurodegenerative disease caused by a genetic mutation present at birth. In the cellular model of Huntington’s disease, the compound prevented the buildup of a harmful RNA molecule. ScienceMission sciencenewshighlights.

New research adds to growing evidence that helping brain cells break down and eliminate their own cellular waste is a promising treatment strategy for a variety of neurodegenerative diseases. In lab experiments, the researchers found that exposure to a novel compound can clear a harmful protein from human neurons modeling frontotemporal dementia — a devastating and ultimately fatal condition — and prevent those neurons from dying.

The study is published in the journal Nature Communications.

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Lab-grown pineal gland organoids produce melatonin, offering a new sleep model

Organoids are miniature, simplified versions of an organ. Over the past two decades, scientists have developed them for the gut, lung, liver, mammary gland, brain, and more. Now, researchers at Yale School of Medicine (YSM) have organoid-ized the pineal gland, a small structure in the brain that regulates sleep patterns through its production of the hormone melatonin.

In a study published in Cell Stem Cell, the researchers demonstrate how pineal gland organoids can be used to study sleep dysfunction in conditions like Angelman syndrome, autism, and depression.

“In a number of neuropsychiatric conditions, severe sleep problems are a major symptom,” says In-Hyun Park, Ph.D., associate professor of genetics at YSM and senior author of the study. “With pineal gland organoids, we may be able to uncover the causes of those sleep disturbances and possibly identify treatments.”

Mapping mutations at scale in a single gene reveals new neurodevelopmental condition

The ability of different genetic variants—changes to one or more building blocks of DNA—to cause disease, and to what extent, has historically been opaque. Geneticist and Crick group leader Greg Findlay has pioneered a new method in the hope of changing this. Called “saturation genome editing,” the new technique involves mapping every single variant in a given gene to work out what it does and pinpoint which changes are responsible for specific disorders.

While Greg was refining these experiments, Nicky Whiffin, associate professor at the University of Oxford, had identified that mutations in a tiny gene were behind a rare inherited neurodevelopmental disorder, known as ReNU syndrome, which impacts brain function, development and motor skills. Children develop this syndrome if a single copy of the RNU4-2 gene is mutated in a specific way.

Nicky initially found that several distinct mutations in a critical region of the gene caused the condition, and she was keen to understand if some of these genetic variants led to more severe disease.

Histone modification clocks for robust cross-species biological age prediction and elucidating senescence regulation

Building upon these insights, we constructed 36 histone modification-based epigenetic clocks, which exhibited robust predictive accuracy (mean Pearson’s r = 0.91) across multiple tissues and marks. Among these, the blood-derived H3K27ac clock emerged as a particularly powerful model, outperforming several established DNA methylation clocks under matched conditions. This performance is remarkable considering that DNA methylation clocks have undergone extensive optimization over the past decade (9, 16, 18), while our histone-based approach represents a first-generation effort.

A distinctive advantage of our histone-based clocks is their resilience to technical and biological noise. When exposed to artificial Gaussian noise, the histone-based clock maintained stable predictive performance, in contrast to the sharp degradation observed in many methylation-based models. This robustness is likely attributable to the broader, structural nature of histone mark signals, which may be less sensitive to local fluctuations than single CpG methylation values. This characteristic makes histone clocks potentially more suitable for noisy, heterogeneous, or clinically derived datasets where sample quality may vary.

The practical utility of our histone-based clocks was further demonstrated by their ability to detect biological age acceleration in leukemia samples and capture age reversal following therapeutic interventions. These applications highlight the potential of histone-based clocks as biomarkers for disease states and treatment responses, offering a complementary approach to existing clinical tools.

APOE4 Increases Neurons’ Excitability Before Symptoms Appear

The pro-Alzheimer’s allele APOE4 makes hippocampal neurons in mice smaller and hyperexcitable. This effect, which resembles epilepsy and accelerated aging, can be mitigated by manipulating a neuronal protein [1].

Before symptoms arise

Alzheimer’s disease begins long before symptoms appear, building silently for decades. The single strongest genetic risk factor for the common, late-onset form of Alzheimer’s is the ε4 variant of the apolipoprotein (APOE) gene, APOE4. Carrying a single copy of this variant (being heterozygous) roughly triples your Alzheimer’s risk; having two copies increases it about 12-fold.

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